Identification of two novel null variants in CLN8 by targeted next-generation sequencing: first report of a Chinese patient with neuronal ceroid lipofuscinosis due to CLN8 variants

Abstract

BackgroundNeuronal ceroid lipofuscinoses (NCLs) are one of the most frequent childhood-onset neurodegenerative pathologies characterized by seizures, progressive cognitive decline, motor impairment and loss of vision. For the past two decades, more than 430 variants in 13 candidate genes have been identified in the affected patients. Most of the variants were almost exclusively reported in Western patients, and very little clinical and genetic information was available for Chinese patients.Case presentationWe report a Chinese boy whose clinical phenotypes were suspected to be NCL, including intractable epilepsy, cognitive and motor decline and progressive vision loss. Using targeted next-generation sequencing, two novel null variants in CLN8 (c.298C > T, p.Gln100Ter; c.551G > A, p.Trp184Ter) were detected in this patient in trans model. These two variants were interpreted as pathogenic according to the variant guidelines of the American College of Medical Genetics and Genomics.ConclusionsThis is the first case report of NCL due to CLN8 variants in China. Our findings expand the variant diversity of CLN8 and demonstrate the tremendous diagnosis value of targeted next-generation sequencing for pediatric NCLs.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0535-7) contains supplementary material, which is available to authorized users.

Neuronal ceroid lipofuscinoses type 8: Expanding genotype/phenotype diversity-first report from Saudi Arabia

“…Our cases are different from the cases reported by Gao et al and Beesley et al, in which their patients had dysphagia, while none of our patients did. 1,8 Furthermore, our cases, mainly patient B, reported an earlier presentation of clinical symptoms and onset of motor disabilities compared with patients in the other reported cases. Cerebellar atrophy was observed in the brain MRIs of all our patients, which was consistent with the previously reported cases of NCL type 8 (Table 1).…”

High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses

“…In silico analysis and ACMG variant classification of all variants are listed in Table S1. There were 52 different variants in seven genes in 91 patients including 11 novel and 41 known variants: CLN1 ( PPT1 ) variants n = 8; CLN2 ( TPP1 ) variants n = 11; CLN3 variants n = 11; CLN5 variants n = 5; CLN6 variants n = 7; CLN7 ( MFSD8 ) variants n = 8; and CLN8 variants n = 2 . The number of missense and truncating variants for each gene is depicted in Figure S3.…”

“…There were 52 different variants in seven genes in 91 patients including 11 novel and 41 known variants: CLN1 (PPT1) variants n = 8 [10][11][12]18,19 ; CLN2 (TPP1) variants n = 11 [12][13][14][20][21][22][23] ; CLN3 variants n = 11 9,12,15,24,25 ; CLN5 variants n = 5 12,21,26 ; CLN6 variants n = 7 12,21,27,28 ; CLN7 (MFSD8) variants n = 8 12 and CLN8 variants n = 2. 17,30 The number of missense and truncating variants for each gene is depicted in Figure S3. The most common variant type was truncating in CLN3, CLN5, and CLN6.…”

“Atypical” Phenotypes of Neuronal Ceroid Lipofuscinosis: The Argentine Experience in the Genomic Era

“…DNA variants in the congenital phenotype cause deleterious effects on the sequence or expression of CLN8, such as loss of initial codon, small exonic indels, frameshifts, stop-gain variants, and large chromosomal deletions. [22,51,[68][69][70][71][72] CLN8 forms the EGRESS complex together with protein CLN6, which participates in the lysosomal biogenesis by transporting soluble lysosomal enzymes to the ERGIC compartment. [73,74] In addition, it is involved in the regulation of key proteins for cellular metabolism.…”